The blood-brain barrier, which results from the low permeability of brain capillaries to most drug molecules, prevents systemically delivered agents from reaching the parenchymal tissue of the brain. Because of this barrier, conventional modes of drug delivery often fail to provide therapeutic drug doses to the brain. Recently, implantable or injectable polymeric controlled release systems have been developed for achieving high concentrations of agents within the brain tissue over an extended period of time (Sabel, et al., 1989, Annals of Neurology, 25:351-356; Saltzman, et al., 1991, Chemical Engineering Science, 46:2429-2444; Reinhard, et al., 1991, Journal of Controlled Release, 16:331-340; Brem, et al., 1991, Journal of Neurosurgery, 74:441-446; Powell, et al., 1990, Brain Research, 515:309-311). Controlled release polymers are designed to release precisely defined quantities of agents over an extended period. When these polymeric systems are inserted directly into the brain tissue, they release a biologically active agent into the brain extracellular space--already past the blood-brain barrier--where they can diffuse within the tissue and provide their therapeutic effect.
While controlled release may be important for treating certain disease of the brain with some specific agents, it has important limitations. Therapeutic agents are released into the brain extracellular space. To be effective, the released agent must diffuse within the extracellular space to reach its site of action. In many cases, this site of action may be many millimeters or centimeters from the polymer matrix. Unfortunately most agents of interest will be removed from the brain by the capillary system or destroyed by brain metabolic processes before they can diffuse far enough to be effective. For example, five chemotherapeutic compounds (hydroxyurea, MTX, thiotepa, BCNU, and cytosine arabinoside) penetrated only 1-5 mm from the ependymal surface following intrathecal perfusion (Blasberg, et al., 1975, J. Pharmacol. Exp. Ther., 195:73-83). Autoradiography following surgically implantation of degradable radiolabeled BCNU-loaded polymers in rabbits revealed that the bulk of the BCNU was within several mm of the implant site (Grossman, et al., 1992, J. Neurosurg., 76:640-647). Similarly, the diffusion distance for cisplatin was &lt;1 mm following direct microinfusion in the rat brain (Morrison, et al., 1986, J. Pharm. Sci., 75:120-128). These small penetration distances for anticancer drugs in brain tissue may limit the effectiveness of polymer matrices for tumor therapy. This limitation may be particularly significant for the treatment of glioblastoma, which can recur several cm from the original primary tumor site (Hochberg, et al., 1980, Neurology 30:907-911).
Thus there is a need in the art for drug delivery vehicles which achieve a larger area of penetration of drug than simple drug-releasing polymer matrices.